JP2533290B2 - New peptide compounds - Google Patents

Abstract

The invention relates to the compounds of formula (I): <IMAGE> in which: R1 represents a hydrogen atom or an acyl, alkyl, benzyl, alkoxycarbonyl, benzyloxycarbonyl, phenoxycarbonyl, 5-[(dimethyl)amino]naphthylsulphonyl, alkoxycarbonylmethyl or carboxymethyl group, R2 represents a hydrogen atom or a phenyl, substituted or unsubstituted benzyl, thienyl-3-methyl, (pyrid-2-yl)methyl, diphenylmethyl, fluorenyl, naphthylmethyl, benzocyclobutyl, (dicyclopropylmethyl)methyl, indanyl or cyclo(C3-C7)alkylmethyl group, R'2 represents a hydrogen atom or a benzyl group or else R2 and R'2 together represent C6H5-CH=, R3 represents a cycloalkyl, aminobenzyl, amidinobenzyl, guanidinobenzyl, aminophenyl, amidinophenyl, guanidinophenyl or substituted alkyl group, R4 and R5 each represent a hydrogen atom or an alkyl group, or <IMAGE> forms a boronic ester of pinanediol, A represents any one of the groups as defined in the description. These compounds are useful as inhibitors of trypsin-like serine proteases such as thrombin.

Description

Detailed Description of the Invention

The present invention relates to peptide compounds derived from boronic acids, a process for their preparation, and pharmaceutical compositions containing them, and their use as inhibitors of trypsin-like serine proteases.

[0002] Thrombin, one of the serine proteases, is the most important enzyme of coagulation and plays a central role in the pathology of venous and arterial thrombosis. This is F. Toti et al. (Sang, Thrombos
e, Vaisseaux, 4, 483-494, 199
2) and Rayleigh (TM. REILLY) et al. (Bl
good Coagulation and Fibri
Nolysis, 3, 513-517, 1992).

Antithrombotic approaches are more effective and less dangerous than current treatments. Direct inhibitors of thrombin currently in clinical development have many advantages over heparin. However, these substances (hirudin and hirulog-1)
g-1)) has the disadvantage of not being active on oral administration.

Furthermore, a peptide containing the sequence (D) Phe-Pro-Arg present in fibrinogen is
It is known to be an inhibitor of the catalytic site of thrombin (C. KETTER et al., J. Bio.
l. Chem. 265 (30), 18289-182.
97, 1990). Peptide compounds derived from boronic acid and exhibiting antithrombotic activity have already been described in the literature. This applies more particularly to the compounds described in EP 293,881 and EP 471,651. Furthermore, Hussein (MA HUSSAI
N) et al. Have shown that Ac- (D) Phe-Pro-Arg-boronic acid (boronic acid) is a thrombin inhibitor (Peptides, 12, 1153).
-1154, 1991).

Therefore, it has been particularly useful to synthesize novel serine protease inhibitors in order to improve the activity and selectivity of the compounds already described in the literature and their activity via oral administration.

More particularly, the invention relates to compounds of formula (I):

[Chemical 21]

Where R₁Is a hydrogen atom or a straight chain or
Branched chain (C₁-C₆) Acyl, straight chain or branched chain (C₁
-C₆) Alkyl, benzyl, straight or branched (C₁
-C ₆) Alkoxycarbonyl, benzyloxycarbo
Nyl, phenoxycarbonyl, 5-[(dimethyl) -a
Mino] naphthylsulfonyl, alkoxycarbonylmethy
Or a carboxymethyl group,

R₂Is a hydrogen atom or one of the following groups
Is -phenyl, -benzyl (unsubstituted or phenyl ring
Above one or more halogen atoms or straight chains
Or branched chain (C₁-C₆) Alkyl, straight or branched
(C₁-C₆) Alkoxy, hydroxyl or bisic
Rooct-1-yl (unsubstituted or hydro
Xyl or linear or branched (C₁-C ₆) Alkoki
Substituted with a group) substituted with a group), -thienylmethyl, -pyridylmethyl, -diphenylmethyl, -fluorenyl, -naphthylmethyl, -benzocyclobutyl,-(dicyclopropylmethyl) methyl,- Indanyl, or- (C₃-C₇Cycloalkyl) methyl,

[0009] R _'2 is a hydrogen atom or a benzyl group, or R ₂ and R' ₂ are together _{C 6 H 5 -CH =, R} 3 is one of the following groups: -Straight or branched (C ₁ -C ₆ ) alkoxy, phenoxy, guanidino, amidino, amino, tetrahydro-2-furyl or a straight or branched chain substituted with a (C ₃ -C ₇ ) cycloalkyl group ( C ₂ -C ₄₎ alkyl, - guanidinophenyl, amidinophenyl, aminophenyl, - guanidino benzyl, amidino benzyl, aminobenzyl or, - (C ₃ -C ₇₎ cycloalkyl,

R ₄ and R ₅ are each a hydrogen atom or a linear or branched (C ₁ -C ₆ ) alkyl group, or

[Chemical formula 22] Forms a boronic ester of pinanediol and A is one of the following groups:

[Chemical formula 23] In the formula, A ₁ is a cyclic structure selected from the following structures, together with the nitrogen atom and carbon atom bonded thereto: -Perhydroindole, 2-Azabicyclo [2.2.2] octane,- 2-azabicyclo [3.3.0] octane, -2-azabicyclo [2.2.1] heptane, -perhydroisoindole, -indoline, -isoindoline, -perhydroquinoline, -perhydroisoquinoline, -1 , 2,3,4-Tetrahydroquinoline, -1,2,3,4-tetrahydroisoquinoline, one or more straight or branched chain (C ₁ -C
₆ ) a thiazolidine optionally substituted with an alkyl group,-

[Chemical formula 24] In the formula, n is 1 or 2,

[0011] R ₆ is a hydrogen atom or a (C ₃ -C ₇₎ cycloalkyl, linear or branched (C ₁ -C ₆₎ alkyl or carboxymethyl group, or R _'6 is a hydrogen atom, Or R ₆ and R ′ ₆ together with the carbon atom which they have to form a (C ₃ -C ₇ ) cycloalkyl group,
₂ is a linear or branched (C ₁ -C ₆ ) alkyl, phenyl, indanyl, (C ₃ -C ₇ ) cycloalkyl (unsubstituted or substituted with one or more methyl groups ), Cycloalkenyl (C ₃ −
C _7), cyclopentadienyl, 2,2,2-trifluoro-1-cyclopentylethyl, bicyclo [2.1.
1] hexyl group, bicyclo [2.2.1] heptyl group,
Or base

[Chemical 25] Wherein X and Y are different and are oxygen or sulfur atoms, or NH or CH ₂ groups, or A ₂ is a hydrogen atom,
(In this case, R ₆ is (C ₃ -C ₇₎ cycloalkyl group, R 'or ₆ is a hydrogen atom, or R ₆ and R' ₆ together with the carbon atoms to which they have (C ₃ -C ₇ ), Under the condition of forming a cycloalkyl group), their enantiomers, diastereomers and optical isomers, and their addition salts with pharmaceutically acceptable acids or bases.

The present invention also relates to a process for preparing a compound of formula (I), the protected amino acid of formula (II) having its isomers separated by standard separation methods as appropriate:

[Chemical formula 26] In the formula, R ′ ₁ is linear or branched (C ₁ -C ₆ ) acyl,
A benzyl, straight-chain or branched (C ₁ -C ₆ ) alkoxycarbonyl, benzyloxycarbonyl or phenoxycarbonyl group, and R ₂ and R ′ ₂ have the same meanings as in formula (I),

Cornig and Geiger (W.KONI
G and R. GEIGER) described peptide binding method (Ber., 103, 788, 1970).
The isomers are separated by standard separation methods as appropriate,
Second protected amino acid of formula (III)

[Chemical 27] Wherein A has the same meaning as in formula (I),

Reacting with a compound of formula (IV):

Embedded image Wherein R ′ ₁ , R ₂ , R ′ ₂ and A have the same meaning as described above,

The acid functional group is deprotected by catalytic hydrogenation to produce a compound of formula (V):

[Chemical 29] Wherein R ′ ₁ , R ₂ , R ′ ₂ and A have the same meaning as described above,

To produce 1,3-in anhydrous medium
A compound of formula (VI): reacted with N-hydroxysuccinimide in the presence of dicyclohexylcarbodiimide:

Embedded image In the formula, R ′ ₁ , R ₂ , R ′ ₂ and A have the same meanings as described above, and Suc means a succinimide radical.

## STR3 ## which is produced in a basic medium by the formula (VI
Compounds of I):

[Chemical 31] Wherein, R _'3 is one of the following groups: - a halogen atom, a straight or branched chain (C ₁ -C ₆₎ alkoxy, phenoxy, substituted with tetrahydro-2-furyl or cycloalkyl group and are linear or branched (C ₂ -C ₄₎ alkyl, - (C ₃ -C ₇₎ cycloalkyl, - phenyl or benzyl are respectively substituted with a halogen atom or a suitably protected amino group, R ' ₄ and R ′ ₅ are each a linear or branched (C ₁ -C ₆ ) alkyl group, or

Embedded image Forms a boronic ester of pinanediol,

Reacting with to produce one of the following: A special case of compounds of formula (I), formula (I /
Compound of a):

[Chemical 33] _{Wherein, R '1, R 2,} R' 2, A, R '4 and R' ₅ have the same meaning as described above, R _'3a represents a linear or branched (C ₂ -C ₄₎ Alkyl group (straight chain or branched chain (C _1-
C ₆₎ alkoxy, phenoxy, tetrahydro-2-furyl or (C ₃ -C ₇₎ substituted with a cycloalkyl group), or (C ₃ -C ₇₎ cycloalkyl group,

Or-a compound of formula (VIII):

Embedded image In the formula, R ′ ₁ , R ₂ , R ′ ₂ , A, R ′ ₄ and R ′ ₅ have the same meanings as described above, and R ′ _3b is one of the following groups.
Are: (C ₂ -C ₄ ) alkyl substituted with a halogen atom, phenyl or benzyl, each substituted with a halogen atom or a suitably protected amino group,

Wherein _R'3b is one of the following groups: -alkyl substituted with a halogen atom, -phenyl or benzyl, each substituted with a halogen atom, and has the formula (VIII) Of the corresponding amidino compound of formula (I / b), which is a special case of the compound of formula (I), is converted by reaction of copper cyanide to the corresponding cyanide and then by the action of aqueous ammonia. :

Embedded image In the formula, R ′ ₁ , R ₂ , R ′ ₂ , A, R ′ ₄ and R ′ ₅ have the same meanings as described above, and R ′ _3c is alkyl substituted with an amidino group, phenyl or A benzyl group,

[0021] is converted to, R _'3b is - when an alkyl group substituted with a halogen atom, by the action of sodium azide, is converted to the corresponding azide compound by then catalytic hydrogenation, formula ( A special case of a compound of I), which is converted to the corresponding amino compound of formula (I / c), or-when it is a phenyl or benzyl group, each substituted with a protected amino group, Deprotected, a special case of formula (I), a compound of formula (I / c):

Embedded image In the formula, R ′ ₁ , R ₂ , R ′ ₂ , A, R ′ ₄ and R ′ ₅ have the same meanings as described above, and R ′ _3d is alkyl substituted with an amino group, phenyl or A benzyl group,

[0022] generates, wherein the compound of formula (I / c) by reaction with cyanamide, amino radicals radicals R _'3d therein undergo conversion to guanidino radical, formula (I) A special case of compounds, the formula (I /
a compound of d);

Embedded image In the formula, R ′ ₁ , R ₂ , R ′ ₂ , A, R ′ ₄ and R ′ ₅ have the same meanings as described above, and R ′ _3e is an alkyl, phenyl or guanidino group substituted, respectively. A benzyl group,

Generate the expression (I / a), if necessary,
The terminal amine group of the compound of (I / b), (I / c) or (I / d) is deprotected and using boronic trichloride in an inert medium, this compound is a compound of formula (I) Which is a special case of the formula (I / e):

[Chemical 38] In the formula, R ′ ₁ , R ₂ , R ′ ₂ , A and R ₃ are represented by the formula (I)
Has the same meaning as in,

Converted to the boronic acid of the formula (I /
a), (I / b), (I / c), (I / d) or (I
The compound of / e) is optionally purified by standard purification methods, -if necessary, its enantiomers are separated by standard separation methods, optionally with pharmaceutically acceptable acids or bases. Is converted to the addition salt of.

The pharmaceutically acceptable acids include hydrochloric acid, hydrobromic acid, sulfuric acid, phosphoric acid, acetic acid, trifluoroacetic acid, lactic acid, pyruvic acid, malonic acid, succinic acid, glutaric acid, fumaric acid, tartaric acid, maleic acid. Acids such as, but not limited to, acids, citric acid, ascorbic acid, methanesulfonic acid, camphoric acid, oxalic acid, and the like.

Pharmaceutically acceptable bases include, but are not limited to, sodium hydroxide, potassium hydroxide, sodium bicarbonate and the like.

The compound of formula (VII) can be obtained by any of the following methods: -The method described by MW RATHKE et al. (J. Organomet. Chem., 122, 14).
5-149, 1976), a compound of formula (IX):

[Chemical Formula 39] Where R ′ ₄ and R ′ ₅ are as previously defined, which results from the organomagnesium compound of formula (X):

Embedded imageIn the formula, R is: -straight chain or branched chain (C₂-C_Four) Alkyl group (straight chain)
Or branched chain (C₁-C ₆) Alkoxy, phenoxy,
Tetrahydro-2-furyl or (C_Five-C₇) Cyclo
Substituted with an alkyl group),-(C₃-C₇) A cycloalkyl group, or-a suitably protected amino group or halogen, respectively.
A phenyl or benzyl group substituted with atoms
,

Reacted with a compound of formula (XI):

Embedded image Where R, R ′ ₄ and R ′ ₅ are as previously defined, which is then added to 1,1,1,3,3,3-hexamethyl in the presence of n-butyllithium. After reaction with disilazane (HMDS) and treatment in acidic medium, one obtains a compound of formula (VII), or-DS.MATTESON et al. (Org
anometrics, 3, 1284-1288,
1984) and W. RATHKE et al. (J. Bi
ol. Chem. 265 (30), 18289-18.
297, 1990), an α-chlorinated boronic acid ester of formula (XII):

Embedded image Wherein R ′ ₄ and R ′ ₅ are as previously defined, p is an integer equal to 3 or 4 and R ′ is a halogen atom or an alkoxy group,

## STR1 ## which is reacted with 1,1,1,3,3,3-hexamethyldisilazane (HMDS) in the presence of n-butyllithium, treated in acidic medium and then of the formula ( The compound of VII) is obtained.

Besides being novel, the compounds according to the invention have particularly useful pharmacological properties.

The compounds of the present invention are potent inhibitors of trypsin-like serine proteases which show superior specificity for thrombin compared to other serine proteases of coagulation. Furthermore, the compounds of the present invention have superior activity upon oral administration than the control compound, DUP714.

Due to these properties, the compound of the present invention is used for the treatment of stable angina or unstable angina, and diseases caused by thrombosis and / or diseases that cause thrombotic complications, myocardial infarction and venous thrombosis. It is also useful for treating arterial thrombosis.

The compounds of the present invention may also be used therapeutically with thrombolytic agents.

The present invention also relates to pharmaceutical compositions containing as active ingredient at least one compound of the formula (I) with one or more suitable non-toxic, inert excipients. The pharmaceutical composition thus obtained is obtained in various forms, most preferably tablets, dragees, hard gelatin capsules, suppositories, oral suspensions and the like.

The appropriate dose depends on the nature and severity of symptoms, administration route, and age and weight of patient. This dose ranges from 1 to 500 mg / day and is administered once or several times.

The following examples illustrate the invention but do not limit it in any way. The starting materials used are known starting materials or are prepared by known methods. Preparations A, B and C are intermediates useful in the preparation of compounds of the present invention.

Preparation A: (+)-α-Pinanediol (R) -1-amino-4-bromo-butylboronate hydrochloride This compound is prepared by the method described by C. KETTNER et al. (J. Biol). Chem., 265 (3
0), 18289-18297, 1990),
Reaction of allyl bromide with catechol borane, then (+)
After transesterification with -α-pinanediol, a synchronized reaction (homol) was performed in the presence of dichloromethyllithium.
It was obtained by reacting with hexamethyldisilazane at the end.

Melting point: 160 ° C. Optical rotation: [α] ²⁵ _D = + 16.5 ° (c = 1%, ethanol) Elemental microanalysis: C% H% N% Cl% Theoretical value 45.88 7.15 3. 82 9.67 Found 45.82 7.09 4.13 9.85

Preparation B: (+)-α-Pinanediol (R)-(1-amino-1-cyclopentyl) methylboronate, hydrochloride Step A: (+)-α-Pinanediol dichloromethylboronate This compound Is a method described by W. RATHKE et al. (J. Organomet. Chem., 12).
2, 145-149, 1976) from dichloromethane and (+)-α-pinanediol and purified by vacuum distillation. Boiling point: 125 ° C (p = 0.4mmHg)

Step B: (+)-α-Pinanediol (cyclopentyl) chloromethyl-boronate 4.75 mmol cyclopentylmagnesium hydrochloride containing 4.75 mmol of the compound obtained in the previous step in 7 ml of anhydrous tetrahydrofuran. , -78 ° C
Add dropwise to the cooled solution. Mix the mixture at 0 ° C 1
After maintaining for a period of time and returning to room temperature, tetrahydrofuran is removed by evaporation. The residue is taken up in an ether / water mixture, the layers are allowed to settle before the ether layer is separated, dried and evaporated to give the expected product, which is taken up in a pentane / dichloromethane (90:10) mixture as solvent. Purify by chromatography on a silica column.

Step C: (+)-α-Pinanediol (R)-(1-amino-1-cyclopentyl) -methylboronate hydrochloride This compound is prepared by the method described by C. KETTNER et al. Biol. Chem., 265 (3
0), 18289-18297, 1990),
Obtained using the compound obtained in the previous step. Optical rotation: [α] ²⁵ _D = + 13.4 ° (c = 1%, methanol)

Preparation C: (+)-α-Pinanediol (R) -1-amino-4-methoxy-butylboronate hydrochloride Step A: Allyl methyl ether 93 mmol of sodium methylate and 85 mmol of allyl bromide, Stir for 12 hours at room temperature in a pressure bottle.
After cooling with dry ice, distillation at atmospheric pressure gives the expected product. Boiling point: 54-55 ° C.

Step B: 4-Methoxybutylcatecholborane 64 mmol product obtained in the previous step and 71.4 mm
ole of catechol borane is refluxed for 18 hours. The expected product is obtained by distillation. Boiling point: 80 ° C. (p = 0.1 mmHg).

Step C: (+)-α-Pinanediol 4-
Aminobutylboronate 22 ml of 20.5 mmol product obtained in the previous step
Dissolved in anhydrous tetrahydrofuran. After cooling to 0 ° C., 20.5 mmol of (+)-α-pinanediol is added to the above mixture. The resulting mixture is 4 at 5-10 ° C.
Leave for 5 minutes, then 45 minutes at room temperature. After evaporating the solvent, 95 ml of hexane are added and the mixture is left in the freezer overnight. The ice-cold precipitate is filtered off and washed with hexane. This precipitate, which converts to an oil at room temperature, is then distilled to give the expected product. Boiling point: 80 ° C. (p = 0.01 mmHg).

Step D: (+)-α-Pinanediol (R) -1-chloro-4-methoxybutyl-boronate

Step E: (+)-α-Pinanediol (R) -1-Amino-4-methoxybutyl-boronate Hydrochloride The products described in Steps D and E are the Ketner (C.KETT).
NER) et al. (J. Biol. Che)
m. 265 (30), 18289-18297).

Abbreviations used in the examples are as follows: Ac for acetyl, Bz for benzyl, Suc for succinimide group, (R) Phe for (R) -phenylalanyl residue, Phi for ( 2S, 3aS, 7aS) -perhydro-2-indole-carbonyl residue, Abo is (3
S) -2-Azabicyclo [2.2.2] octane-3-
Carbonyl residue, Ala is an alanyl residue, Gly is a glycyl residue, Clp is a 1-aminocyclopentylcarbonyl residue of the following formula:

[Chemical 43] Asp is an aspartyl residue, βAla is a β-alanyl residue, Acn is a 2-aminocinamyl residue of the following formula:

[Chemical 44]

Example 1: (+)-α-Pinanediol 1
-(R)-[(Ac- (RS) Phe-Phi) amino] -4-aminobutylboronate methanesulfonate Step A: Ac- (RS) Phe-Phi-OBz Cornig and Geiger (W.KONIG and R.
GEIGER) described peptide binding method (DCC / H
OBT) (Ber., 103, 788, 1970),
73m using anhydrous dimethylformamide as solvent
The expected product is prepared from mol Phi-OBz and Ac- (R) Phe-OH and purified by chromatography on a silica column with a dichloromethane / ethanol (97: 3) mixture as eluent. Yield: 76%

Step B: Ac- (RS) Phe-Phi-OH 25 mm obtained in the previous step in 140 ML ethanol.
2 g of anhydrous palladium / C (10% P
Hydrogenate in the presence of d) under a hydrogen pressure of 4 kg for 12 hours. After removal of the catalyst and filtration, evaporation of the solvent gives the expected product. Yield: 97%

Step C: Ac- (RS) Phe-Phi-OSuc 4.46 mmol of the product obtained in the previous step in 20 ml of anhydrous dichloromethane and 4.46 mmol of dicyclohexylcarbodiimide dissolved in dichloromethane are added in 50 ml of anhydrous solution. 4.46 mmo in dichloromethane
Add to 1 of N-hydroxy-succinimide. The mixture is stirred at room temperature for 12 hours. The dicyclohexylurea formed is filtered off and evaporated to give the expected product.

Step D: (+)-α-Pinanediol 1-
(R)-[(Ac- (RS) Phe-Phi) amino]
-4-Bromobutylboronate 1 mmol of the compound obtained in preparation A and 1 mmol of the compound obtained in the previous step in 10 ml of anhydrous dichloromethane are placed at -20 ° C under an argon atmosphere. Next 14
ml triethylamine is added dropwise and the mixture is -2.
Hold at 0 ° C. for 30 minutes. After returning to room temperature, the mixture is stirred overnight under an atmosphere of argon. After taking up the product in ethyl acetate, the organic layer is washed with water, sodium bicarbonate, water, 0.2
Wash with N hydrochloric acid and finally with water, dry and evaporate. The expected product is obtained after purification on "Sephadex". Yield: 90%

Step E: (+)-α-Pinanediol 1-
(R)-[(Ac- (RS) Phe-Phi) amino]
-4-Azidobutylboronate 1.5 mmol of the product obtained in the previous step in 3 ml of anhydrous dimethylformamide are left at 100 ° C. for 4 hours in the presence of 3 mmol of sodium azide. 1 at room temperature
After standing for 2 hours, the mixture is taken up in an ethyl acetate / water mixture, the organic layer is washed several times, dried and evaporated to give the expected product. Yield: 95%

Step F: (+)-α-Pinanediol 1-
(R)-[(Ac- (RS) Phe-Phi) amino]
-4-Aminobutylboronate methanesulfonate 1.4 obtained in the previous step in 25 ml of anhydrous methanol
mmol compound in the presence of 1.4 mmol methanesulfonic acid, 50 mg palladium / C (10% P
Hydrogenate for 2 hours using d) as catalyst. After filtering off the catalyst, washing and evaporating the filtrate, the expected product is obtained. Yield: 95%

Example 2: (+)-α-Pinanediol 1
-(R)-[(Ac- (RS) Phe-Phi) amino] -4-guanidinobutylboronate methanesulfonate 1.3 mmol of the compound obtained in Example 1 and 10.3
The mmol cyanamide is refluxed in 8 ml absolute ethanol for 10 days. After evaporation of the ethanol and passage through a Sephadex medium, it is taken up in methanol and the expected product is obtained. Yield: 91%

Example 3: 1- (R)-[(Ac- (R
S) Phe-Phi) amino] -4-guanidinobutylboronic acid acetate A compound of 1.2 MMOL obtained in Example 2 in 30 ml of anhydrous dichloromethane was added under argon atmosphere at -78.
Cool to ° C. Then 4.8 mmol of boronic trichloride is added dropwise over 30 minutes. The temperature is brought to 0 ° C. and the mixture is stirred for 30 minutes. Then 10 ml of ice-cold water is added and after stirring for 15 minutes the mixture is allowed to come to room temperature. After settling down, the organic layer was separated and 10 ml of water / acetic acid (9
0:10) Extract with mixture. The remaining aqueous layers are washed with ether and the combined aqueous layers are evaporated. The residue is purified on biogel (Bio-gel) using a water / acetic acid (90:10) mixture as eluent to give the expected product, which is lyophilized.

Elemental microanalysis: C% H% N% theoretical value 56.45 7.54 14.63 actual value 54.71 7.26 13.59

Example 4: 1- (R)-[(Ac- (R)
Phe-Phi) Amino] -4-aminobutylboronic acid acetate This compound was obtained according to the same procedure as described in Example 3, using the compound of Example 1 as the starting material.

Example 5: (+) α-Pinanediol (R)-[(Ac- (R) Phe-Phi) amino]-
Cyclopentyl) methylboronate Steps A to C: These steps are the same as Step A of Example 1.

Step D: This compound was obtained according to the method described in Step D of Example 1 from the compound obtained in Step C and the compound obtained in Preparation B. Yield: 90%

Example 6: (R)-[(Ac- (R) Ph
e-Phi) Amino] cyclopentyl) methylboronic acid acetate This compound was obtained according to the method described in Example 3 using the compound of Example 5 as the starting material.

The compounds of Examples 7 to 14 were obtained according to the same procedure as described in Example 1 with the corresponding starting materials. Example 7: (+)-α-Pinanediol 1- (R)-
[(Ac- (RS) Phe-Abo) amino] -4-aminobutylboronate methanesulfonate Example 8: (+)-α-Pinanediol 1- (R)-
{[(Ac- (R)-(cyclohexyl) Ala- (N
-Cyclopentyl) Gly] amino} -4-aminobutylboronate methanesulfonate Example 9: (+)-α-Pinanediol 1- (R)-
{[Ac- (R) Phe- (N-cyclobutyl) Gl
y] amino} -4-aminobutylboronate methanesulfonate Example 10: (+)-α-Pinanediol 1- (R)-
{[Ac- (RS) Phe- (N-cyclohexyl) G
ly] amino} -4-aminobutylboronate methanesulfonate Example 11: (+)-α-Pinanediol 1- (R)-
{[Ac- (RS) Phe- (N-cyclopentyl) G
ly] amino} -4-aminobutylboronate methanesulfonate Example 12: (+)-α-Pinanediol 1- (R)-
{[Ac- (R) Phe- (N-cyclopentyl) Gl
y] amino} -4-aminobutylboronate methanesulfonate Example 13: (+)-α-Pinanediol 1- (R)-
{[Ac- (S) Phe- (N-cyclopentyl) Gl
y] amino} -4-aminobutylboronate methanesulfonate Example 14: (+)-α-Pinanediol 1- (R)-
{[Ac- (RS) Phe- (N- (RS) indan-
1-yl) Gly] amino} -4-aminobutylboronate methanesulfonate

Examples 15 to 22 were synthesized according to the same method as described in Example 2 with the corresponding starting materials. Example 15: (+)-α-Pinanediol 1- (R)-
[(Ac- (RS) Phe-Abo) amino] -4-guanidinobutylboronate benzenesulfonate From the compound of Example 7. Example 16: (+)-α-Pinanediol 1- (R)-
{[(Ac- (R)-(cyclohexyl) Ala- (N
-Cyclopentyl) Gly] amino} -4-guanidinobutylboronate benzenesulfonate From the compound of Example 8. Example 17: (+)-α-Pinanediol 1- (R)-
{[Ac- (R) Phe- (N-cyclobutyl) Gl
y] Amino} -4-guanidinobutylboronate benzene sulfonate From the compound of Example 9. Example 18: (+)-α-Pinanediol 1- (R)-
{[Ac- (RS) Phe- (N-cyclohexyl) G
ly] amino} -4-guanidinobutylboronate benzene sulfonate From the compound of Example 10. Mass spectrum: FAB ⁺ : [M + H]: m / z = 63
6 Example 19: (+)-α-Pinanediol 1- (R)-
{[Ac- (RS) Phe- (N-cyclopentyl) G
ly] amino} -4-guanidinobutylboronate benzenesulfonate From the compound of Example 11. Mass spectrum: FAB ⁺ : [M + H]: m / z = 62
2 Example 20: (+)-α-Pinanediol 1- (R)-
{[Ac- (R) Phe- (N-cyclopentyl) Gl
y] Amino} -4-guanidinobutylboronate trifluoroacetate From the compound of Example 12. Mass spectrum: FAB ⁺ : [M + H]: m / z = 62
2 Example 21: (+)-α-Pinanediol 1- (R)-
{[Ac- (S) Phe- (N-cyclopentyl) Gl
y] Amino} -4-guanidinobutylboronate benzene sulfonate From the compound of Example 13. Example 22: (+)-α-Pinanediol 1- (R)-
{[Ac- (RS) Phe- (N- (RS) indan-
1-yl) Gly] amino} -4-guanidinobutylboronate benzenesulfonate From the compound of Example 14.

The compounds of Examples 23 to 30 were synthesized according to the same method as described in Example 3 with the corresponding starting materials. Example 23: 1- (R)-[(Ac- (RS) Phe-
Abo) Amino] -4-guanidinobutylboronic acid acetate From the compound of Example 15. Mass spectrum: FAB ⁺ : [M + glycerol-2H ₂ O + H] ⁺ : m
/ Z = 557 Example 24: 1- (R)-{[(Ac- (R)-(cyclohexyl) Ala- (N-cyclopentyl) Gly]
Amino} -4-guanidinobutylboronic acid acetate From the compound of Example 16. Mass spectrum: FAB ⁺ : [M + glycerol-2H ₂ O + H] ⁺ : m
/ Z = 586 Example 25: 1- (R)-{[Ac- (R) Phe-
(N-Cyclobutyl) Gly] amino} -4-guanidinobutylboronic acid acetate From the compound of example 17. Mass spectrum: FAB ⁺ : [M + glycerol-2H ₂ O + H] ⁺ : m
/ Z = 566 Example 26: 1- (R)-{[Ac- (RS) Phe-
(N-Cyclohexyl) Gly] amino} -4-guanidinobutylboronic acid methanesulfonate From the compound of Example 18. Elemental microanalysis: C% H% N% Theoretical value 55.52 7.71 14.94 Actual value 56.20 7.25 14.54 Example 27: 1- (R)-{[Ac- (RS) Phe −
(N-Cyclopentyl) Gly] amino} -4-guanidinobutylboronic acid acetate From the compound of Example 19. Mass spectrum: FAB ⁺ : [M + glycerol-2H ₂ O + H] ⁺ : m
/ Z = 580 Example 28: 1- (R)-{[Ac- (R) Phe-
(N-Cyclopentyl) Gly] amino} -4-guanidinobutylboronic acid acetate From the compound of example 20. Mass spectrum: FAB ⁺ : [M + glycerol-2H ₂ O + H] ⁺ : m
/ Z = 580 Example 29: 1- (R)-{[Ac- (S) Phe-
(N-Cyclopentyl) Gly] amino} -4-guanidinobutylboronic acid acetate From the compound of Example 21. Mass spectrum: FAB ⁺ : [M + glycerol-2H ₂ O + H] ⁺ : m
/ Z = 580 Example 30: 1- (R)-{[Ac- (RS) Phe-
(N- (RS) indan-1-yl) -Gly] amino} -4-guanidinobutylboronic acid acetate From the compound of Example 22. Mass spectrum: FAB ⁺ : [M + glycerol-2H ₂ O + H] ⁺ : m
/ Z = 593 Example 31: (+)-α-Pinanediol 1- (R)-
[(Ac- (RS) Phe-Phi) -amino] -4-
Methoxybutylboronate This compound was prepared according to the method described in Example 1 (steps A to D) instead of the compound obtained in preparation A in step D
Was synthesized using the compound obtained in Preparation C. Elemental microanalysis: C% H% N% Theoretical value 67.63 8.43 6.76 Actual value 67.16 8.39 7.10 Example 32: 1- (R)-[(Ac- (RS) Phe. −
Phi) Amino] -4-methoxy-boronic acid This compound is prepared according to the method described in Example 3 to Example 3
Was synthesized from the compound obtained in 1. Mass spectrum: FAB ⁺ : [M + glycerol-H ₂ O + H] ⁺ : m /
z = 543 Example 33: (+)-α-Pinanediol 1- (R)-
{[N- (5-Dimethylamino-1-naphthalenesulfonyl) Gly-Phi] amino} -4-aminobutylboronate benzenesulfonate

Steps A to D: These Steps A to D are the same as Steps A to D of Example 1, except that in Step A, Ac
-(R) Phe-OH instead of Boc-Gly-OH
Is used. Step E: (+)-α-Pinanediol 1- (R)-
[(Gly-Phi) amino] -4-bromobutylboronate trifluoroacetate Dissolve 6.64 mmol of product obtained in the previous step in 20 ml of dichloromethane at 0 ° C., 53 mmol
Deprotection in the presence of trifluoroacetic acid. After stirring for 1 hour and evaporating the solvent and drying at room temperature for 24 hours, the expected product is obtained.

Step F: (+)-α-Pinanediol 1-
(R)-{[N- (5-Dimethylamino-1-naphthalenesulfonyl) Gly-Phi] amino} -4-bromobutylboronate Dissolved in 100 ml of tetrahydrofuran and protected from light, obtained in the previous step. To 6.53 mmol of compound is added 19.8 mmol of triethylamine. 5
After stirring for a minute, 6.6 mmol of dansyl chloride is added in small portions. Stir 4 h, evaporate the solvent, take up the residue in ethyl acetate, wash with sodium bicarbonate, evaporate and purify on a Sephadex LH-20 column using methanol as eluent to give the expected product. Is obtained.

Steps G and H: These steps are the same as steps E and F of Example 1, but benzenesulfonic acid is used instead of methanesulfonic acid. Example 34: (+)-α-Pinanediol 1- (R)-
{[N- (5-Dimethylamino-1-naphthalenesulfonyl) Gly-Phi] amino} -4-guanidinobutylboronatebenzenesulfonate According to the method described in Example 2, the expected product from the compound of Example 33. Is obtained. Mass spectrum: FAB ⁺ (I ⁺ ): [M + H] ⁺ : m
/ Z = 750

Example 35: 1- (R)-{[N- (5-
Dimethylamino-1-naphthalenesulfonyl) Gly-
Phi] amino} -4-guanidinobutylboronic acid diacetate The compound of Example 34 is followed according to the method described in Example 3 to give the expected product. Mass spectrum: FAB ⁺ (I ⁺ ): [M + H + glycerol-H ₂ O]
⁺ : M / z = 672

Examples 36 to 61 were obtained according to the method of Example 3 from the corresponding starting materials. Example 36: 1- (R)-{[Ac- (R) Phe-
(N-Cyclopenta-2,4-dienyl) Gly] amino} -4-guanidinobutylboronic acid acetate Example 37: 1- (R)-{[Ac- (R) Phe (N
-Bicyclo [2.1.1] hex-5-yl) Gly]
Amino} -4-guanidinobutylboronic acid acetate Example 38: 1- (R)-{[Ac- (R) Phe-
(N-1,2-oxazolidin-3-yl) Gly] amino} -4-guanidinobutylboronic acid acetate Example 39: 1- (R)-{[Ac- (R) Phe-
(N-Cyclopent-3-enyl) Gly] amino}-
4-guanidinobutylboronic acid acetate Example 40: 1- (R)-{[Ac- (R) Phe-
(N-Cyclopent-2-enyl) Gly] amino}-
4-guanidinobutylboronic acid acetate Example 41: 1- (R)-{[Ac- (R) Phe-
(N- (1-Methyl) cyclopentyl) Gly] amino} -4-guanidinobutylboronic acid acetate Example 42: 1- (R)-{[Ac- (R) Phe-
(N- (3,5-dimethyl) cyclopentyl) Gly]
Amino} -4-guanidinobutylboronic acid acetate Example 43: 1- (R)-{[Ac- (R) Phe-
(N- (2,2-dimethyl) cyclopentyl) Gly]
Amino} -4-guanidinobutylboronic acid acetate Example 44: 1- (R)-{[Ac- (R) Phe-
(N- (1-Cyclopentyl) 2,2,2-trifluoroethyl) -Gly] amino} -4-guanidinobutylboronic acid acetate Example 45: 1- (R)-{[Ac- (R) Phe −
(N-Cyclopropyl) Gly] -amino} -4-guanidinobutylboronic acid acetate Example 46: 1- (R)-{[Ac- (R) Phe-
(N- (3-methyl) cyclobutyl) Gly] amino}
-4-guanidinobutylboronic acid acetate Example 47: 1- (R)-{[Ac- (R) Phe-
(N- (1-ethyl) propyl) Gly] amino} -4
-Guanidinobutylboronic acid acetate Example 48: 1- (R)-{[Ac- (R) (3-thienyl) Ala- (N-cyclopentyl) Gly] amino} -4-guanidinobutylboronic acid acetate Implementation Example 49: 1- (R)-{[Ac- (R) (diphenyl) Ala- (N-cyclopentyl) Gly] amino}
-4-guanidinobutylboronic acid acetate Example 50: 1- (R)-{[(R) Phe- (N-cyclopentyl) Gly] amino} -4-guanidinobutylboronic acid acetate Example 51: 1- (R)-{[(N-methyl) (R) P
he- (N-cyclopentyl) Gly] amino} -4-
Guanidinobutylboronic acid acetate Example 52: 1- (R)-{[Ac- (R) (benzocyclobutyl) Gly- (N-cyclopentyl) Gly]
Amino} -4-guanidinobutylboronic acid acetate Example 53: 1- (R)-{[(N-methyl)-(R)
-Phenyl Gly- (N-cyclopentyl) Gly] amino} -4-guanidinobutylboronic acid acetate Example 54: 1- (R)-{[(N-methoxycarbonylmethyl)-(R) -Phe- (N -Cyclopentyl)
Gly] amino} -4-guanidinobutylboronic acid acetate Example 55: 1- (R)-{[Ac [di (phenylmethyl)] Gly- (N-cyclopentyl) Gly] amino} -4-guanidinobutylboro Nickic Acid Acetate Example 56: 1- (R)-{[Ac- (R) Phe-
(Cyclopentyl) Gly] amino} -4-guanidinobutylboronic acid acetate Example 57: 1- (R)-{[Ac- (R) Phe-C
Ip] -4-guanidinobutylboronic acid acetate Example 58: 1- (R)-{[Ac- (R) Phe-
(N-Cyclopentyl) Ala] amino} -4-guanidinobutylboronic acid acetate Example 59: 1- (R)-{[Ac- (R) Phe-
(N-Cyclopentyl) Asp] -Amino} -4-guanidinobutylboronic acid acetate Example 60: 1- (R)-{[Ac- (R) Phe-
(N-Cyclopentyl) -β-Ala] -amino} -4
-Guanidinobutylboronic acid acetate Example 61: 1- (R)-{[Ac- (Acn)-(N
-Cyclopentyl) Gly] -amino} -4-guanidinobutylboronic acid acetate

Pharmacological test of compounds of the invention

Example 62: Antithrombotic activity The model of experimental thrombosis used is venous thrombosis induced in male Wistar rats by ligation of the inferior vena cava under the left renal vein. The test animal is Brietal ^™
(Sodium mesohexital
Al sodium)) is intraperitoneally administered at a dose of 1 mg / kg for anesthesia. Next, ligation is performed. Test compounds were injected intravenously 15 minutes before ligation. Twenty-five minutes after the ligation, the vein was incised to collect the thrombus, which was transferred to an oven at 37 ° C for 12 hours and then weighed. The compounds of the invention were tested at doses of 0.1, 0.25 and 0.5 mg / kg and compared to DUP714 used as a control compound. The results of this test show that the compounds of the invention significantly reduce the weight of thrombus, which is due to the control compound DUP7.
It is shown to be as large as that observed with 14 injections. At 0.25 mg / kg, the compounds of the invention inhibit thrombus formation by about 50%.

Example 63: Anticoagulant activity, determination of thrombin time in rat and human In the presence of a standard amount of thrombin, normal plasma clots for a certain time, called the thrombin time (TT). The extension of this time reflects the abnormalities in fibrin formation (coagulation). Phenobarbital sodium (60 mg / kg, ip) in Sprague-Dawley rats
Anesthetize with, catheterize the carotid artery, take a blood sample and place in trisodium citrate solution (0.109M). Blood samples are centrifuged (3000 g, 15 min) to obtain platelet poor plasma. A venous blood sample is also taken from the flexion of a human arm. Anticoagulation of samples and preparation of platelet poor plasma are the same as for rat blood.

Thrombin time is Prest
Obtained using thrombin reagent, coagulometer (coag
It is calculated automatically by using the (ulometer). Plasma (90 μl) antagonist or solvent (10 μl)
And then incubate at 37 ° C. for 2 minutes. 1
Start the clock by adding 00 μl thrombin.
Under these conditions, the TT value obtained with control plasma is about 30 seconds in rat and about 20 seconds in human. Antagonist activity is assessed by the ability to prolong thrombin time relative to controls. Under these conditions, the compounds of the invention prolong thrombin time by a factor of 50 or more. The effect of the inhibitor is measured and the concentration that doubles the thrombin time (CTT2) is determined. The results are shown in the table below:

Table 1 Compounds Rat Human CTT2 (μM) CTT2 (μM) Example 3 0.23 0.07 Example 23 0.17 0.11 Example 27-0.20 Example 28-0.19 Control: DUP714 0.32 0.18, ie for the compound of Example 23, the concentration required to double the thrombin time in rats was the same as that of the control compound (DU).
It is half of the concentration obtained in P714). For the compound of Example 3, the concentration required to double thrombin time in humans is 2.5-fold less than the concentration obtained with the control compound (DUP714).

Example 64: Inhibition of thrombin and inhibition of coagulation and fibrinolytic serine proteases Human thrombin (Sigma, specific activity 323)
Purified fibrinogen (4 mM, Stago) (F) to assess the in vitro inhibitory activity of boro-arginine compounds with respect to 0 NIHU / mg).
g) or the chromogenic substrate HD-Phe-Pip-Arg
-PNa (44 mM, S2238, mold (Kabi))
Was added to an aliquot (0.7 or 2 nM) of thrombin pre-incubated (20 ° C., 10 min) with or without test inhibitor.

To evaluate the in vitro selectivity of these compounds for serine proteases with different fibrinolysis and coagulation, the same test design was used with purified human plasmin (2
nM, Stago), purified human activated protein C (2nM, Stago), purified human activated factor X (2nM, Stago)
o)), tissue plasminogen activator (2 nM,
Different peptidyl para-nitroanilides were applied as substrates to Calbiochem), purified human urokinase (2nM, Sigma), and purified human plasma kallikrein (2nM, Calbiochem): <plasmin <. Glu-Phe-Lys-pNA (0.50m
M, S2403, mold (Kabi), N for factor Xa
-Cbo-Arg-Gly-Arg-pNA (0.38
<Glu-Pro-Arg-pNa (0.52) in mM, S2765, mold (Kabi), activated protein C
mM, S2366, mold (Kabi), kallikrein with HD-Pro-Phe-Arg-pNa (0.45
mM, S2302, mold (Kabi), HD-Il
e-Pro-Arg-pNA (0.48 mM, S228
8, mold (Kabi), <Glu-Gly-Arg-
pNA (0.56 mM, S2444, mold (Kab
i)).

The inhibitor, enzyme and substrate are in the same buffer (0.01 mM phosphate buffer, pH 7.4, 0.12).
M sodium chloride and 0.05% bovine serum albumin) and then placed in polystyrene microplates in a volume of 50 μl. Thrombin,
Alternatively, fibrin produced by para-nitroaniline released by the action of serine proteases is measured spectrophotometrically at 405 nm after reaction for 15 to 30 minutes at 20 ° C.

The table below shows the reference compound (DUP714).
And in the presence of the compounds of Examples 25, 27 and 28,
The concentration of the compound that inhibits the enzyme activity by 50% (IC ₅₀ ) is shown relative to the compound-free control. The results are shown in Examples 25 and 2
Compound 8 is shown to be a more potent inhibitor of human thrombin with respect to human fibrinogen than the control compound. The compounds of Examples 25, 27 and 28 are related to coagulation and fibrinolytic serine proteases.
The selectivity is superior to the reference compound DUP714.

[Table 2] Example 65: Measurement of anticoagulant activity ex vivo, oral administration of compounds (conscious rats) -Fasted OFA rats are anesthetized with ether. The cordal artery is exposed and the catheter is inserted. Citric oxidation on the catheter (1/40)
Blow in a physiological solution. After placing the catheter, place the rat in a restraint cage and add 1.5 ml of arterial blood to 0.109.
Collect in M citric acid (1/9). -One hour after the rat was awake, 10 mg /
The test compound is administered orally in a single dose of kg. -Then arterial blood samples (1.5 ml) are taken at 30, 60 and 2 hours. -At the time of each sample collection, re-inject the rat with 1.5 ml of physiological solution. -Prepare plasma by centrifuging blood tubes at 3000 g for 15 minutes. After adding Prest thrombin, the onset time of the clotting phenomenon is measured. The compounds of the invention prolong thrombin time (TT) in a dose-responsive manner, their activity in the first 2 hours being comparable or greater than that obtained with the control compound (DUP714). The results, shown in the table below, demonstrate the fold increase in thrombin time.

[Table 3]

Example 66: Measurement of anticoagulant activity ex vivo, intravenous administration of compound (iv) OFA rats, fasted or not, were pentobarbital (60 mg / kg i.p.). Administration). The carotid artery and jugular vein are exposed and catheterized.
The catheter is flushed with citrated (1/40) physiological solution. After placing the catheter, 1.5 ml of arterial blood is collected in 0.109 M citric acid (1/9). -30 minutes later the test compound is administered intravenously in a volume of 1 ml. -Next 1 minute 30 seconds, 5 minutes, 15 minutes, 30 minutes and 60 minutes
An arterial blood sample (1.5 ml) is taken at the minute. -At the time of each sample collection, reinject the rat with 1.5 ml of citrated physiological solution through the carotid artery. -Centrifuge the test tube of blood at 3000 g for 15 minutes (preparation of plasma). 100 μl of plasma are incubated with 100 μl of activated cephalin. After the addition of 100 μl of calcium, the onset time of the coagulation phenomenon is measured. Compounds of the invention tested at a dose of 0.5 mg / kg dose-dependently activate activated cephalin time (ACT)
Extend. Its anticoagulant activity depends on the control compound (DUP7
14) or greater. The prolongation of ACT observed with the compounds of the invention is still significant 60 minutes after administration. The results, shown in the table below, show the magnification for increasing clotting time.

[Table 4]

Example 67: Anticoagulant activity and thrombocytopenia in dogs (PO) The compounds were orally administered at 2 and 4 hours after treatment of dogs, and blood was collected through a vein. Plasma is prepared, platelets are counted, and thrombin time is measured. The table below shows that DUP 714 prolonged TT at a concentration of 2.5 mg / kg, but caused significant thrombocytopenia. The compound of the present invention has a DU concentration of 5 mg / kg.
It showed greater TT prolongation than P714 and had no effect on platelet count.

[Table 5]

Pharmaceutical Composition Example 68: Pharmaceutical Composition Preparation Method of 1000 Tablets Containing 10 mg: Compound of Example 3 ... 10 g Hydroxypropylcellulose ....・ ・ ・ ・ 2g Wheat starch ・ ・ ・ ・ 10g Lactose ・ ・ ・ ・ 100g Magnesium stearate ・・ ・ ・ ・ ・ ・ 3g Talc ・ ・ ・ ・ ・ ・ 3g

 ─────────────────────────────────────────────────── ─── Continuation of the front page (72) Inventor Tony Verblan, Verneuil, France, Ruaris Chidbrian 60 Bi (72) Inventor, Serge Simon, France Conflan Saint Onoran, Rudesile Clement, 43 (72) Inventor, Alain Lupin Savoniere, France (No address) (72) Inventor Bernard Portovin Elancourt, France Ryu Frederic Passy 6 (56) References JP-A-1-163185 (JP, A) JP-A-2 -91023 (JP, A) JP 64-63583 (JP, A) JP 60-146900 (JP, A) JP 5-504775 (JP, A) JP 6-184192 (JP, A) )

Claims (13)

(57) [Claims] 1. A compound of formula (I): In the formula, R ₁ is a hydrogen atom or a linear or branched chain (C ₁
-C ₆₎ acyl, linear or branched (C ₁ -C ₆₎ alkyl, benzyl, straight or branched chain (C ₁ -C ₆₎ alkoxycarbonyl, benzyloxycarbonyl, phenoxycarbonyl, 5 - [(dimethylamino) - amino] naphthylsulfonyl, alkoxycarbonyl methyl or carboxymethyl group, R ₂ is one of hydrogen atom or the following group: - phenyl, - benzyl (unsubstituted or substituted, or on the phenyl ring, One or more halogen atoms or straight or branched (C ₁ -C ₆ ) alkyl, straight or branched (C ₁ -C ₆ ) alkoxy, hydroxyl or bicyclooct-1-yl (unsubstituted Or substituted with a hydroxyl or a linear or branched (C ₁ -C ₆ ) alkoxy group) group That), - thienylmethyl, - pyridylmethyl, - diphenylmethyl, - fluorenyl, - naphthylmethyl, - benzocyclobutenol, - (dicyclopropyl) methyl, - indanyl, or - (C ₃ -C ₇ cycloalkyl) methyl: _R'2 is a hydrogen atom or a benzyl group, or R ₂ and _R'2 is C ₆ H ₅ is -CH = together, R ₃ is one of the following groups: - Straight or branched (C ₁ -C ₆ ) alkoxy, phenoxy, guanidino, amidino, amino, tetrahydro-
2-furyl or (C ₃ -C ₇₎ straight or branched chain substituted with a cycloalkyl group (C ₂ -C ₄₎ alkyl, - guanidinophenyl, amidinophenyl, aminophenyl, - guanidino benzyl, amidino benzyl, aminobenzyl or, - (C ₃ -C ₇₎ cycloalkyl: R ₄ and R ₅ are either each a hydrogen atom or a straight or branched chain (C ₁ -C ₆₎ alkyl group, or a ## STR2 ## Forms a boronic ester of pinanediol, and A is one of the following groups: In the formula, A ₁ is a cyclic structure selected from the following structures, together with the nitrogen atom and carbon atom bonded thereto: -perhydroindole, 2-azabicyclo [2.2.2] octane,- 2-azabicyclo [3.3.0] octane, -2-azabicyclo [2.2.1] heptane, perhydroisoindole, indoline, isoindoline, perhydroquinoline, perhydroisoquinoline, -1 , 2,3,4-Tetrahydroquinoline, -1,2,3,4-tetrahydroisoquinoline, one or more straight or branched chain (C ₁ -C
₆ ) Thiazolidine optionally substituted with an alkyl group, In the formula, n is 1 or 2, R ₆ is a hydrogen atom, a (C ₃ -C ₇ ) cycloalkyl, a linear or branched (C ₁ -C ₆ ) alkyl or a carboxymethyl group, and R ′ is ₆ is a hydrogen atom, or R ₆ and R ′ ₆ together with the carbon atoms they have (C
_3- C ₇ ) cycloalkyl group is formed, A ₂ is a straight chain or branched (C ₁ -C ₆ ) alkyl, phenyl, indanyl, (C ₃ -C ₇ ) cycloalkyl (unsubstituted or or substituted with one or more methyl groups), cycloalkenyl (C ₃ -
C _7), cyclopentadienyl, 2,2,2-trifluoro-1-cyclopentylethyl, bicyclo [2.2.
1] hexyl group, bicyclo [2.2.1] heptyl group,
Or the group In the formula, X and Y are different and each is an oxygen or sulfur atom, or an NH or CH ₂ group, or A ₂ is a hydrogen atom (in this case, R ₆ is (C ₃ -C ₇ )).
A cycloalkyl group, R ′ ₆ is a hydrogen atom, or R ₆ and R ′ ₆ together with the carbon atoms they carry form a (C ₃ -C ₇ ) cycloalkyl group, The antipodes, diastereoisomers or optical isomers, or their addition salts with pharmaceutically acceptable acids or bases. 2. A compound of the formula (I) according to claim 1, wherein R ₁ is an acetyl group, its antipode, diastereoisomer or optical isomer, or a pharmaceutically acceptable acid or base. Its addition salt. 3. A compound of the formula (I) according to claim 1, wherein R ₂ is a benzyl group, its antipode, diastereoisomer or optical isomer, or a pharmaceutically acceptable acid or base. Its addition salt. 4. A is a group as defined in claim 1 A compound of formula (I) according to claim 1 which is
Diastereoisomers or optical isomers, or their addition salts with pharmaceutically acceptable acids or bases. 5. A is a group as defined in claim 1 A compound of formula (I) according to claim 1 which is
Diastereoisomers or optical isomers, or their addition salts with pharmaceutically acceptable acids or bases. 6. A compound of formula (I), its enantiomers, diastereoisomers according to claim 4, wherein A ₁ is a perhydroindole ring system together with the nitrogen and carbon atoms attached to it. Alternatively, an optical isomer, or an addition salt thereof with a pharmaceutically acceptable acid or base. 7. The compound of formula (I) according to claim 1, wherein R ₃ is a guanidino (linear or branched C ₂ -C ₄ alkyl) group, its enantiomer, diastereomer or optical. Isomers, or their addition salts with pharmaceutically acceptable acids or bases. 8. A compound of formula (I) according to claim 1, wherein R ₃ is a (C ₃ -C ₇ ) cycloalkyl group, its antipode, diastereoisomer or optical isomer, or as a drug. An addition salt thereof with an acceptable acid or base. 9. 1- (R)-[(Ac- (R) Phe-
Phi) amino] -4-guanidinobutylboronic acid (A
c is acetyl, (R) Phe is (R) -phenylalanyl, Phi is (2s, 3aS, 7aS) -perhydro-
A compound of formula (I) according to claim 1, or an isomer thereof, or an addition salt thereof with a pharmaceutically acceptable acid or base. 10. 1- (R)-{[Ac-Phe- (N
-Cyclopentyl) Gly] amino} -4-guanidinobutylboronic acid acetate (Ac is acetyl, Phe is (RS) or (R) oriented phenylalanyl, Gly
Is glycyl), or a compound of formula (I) according to claim 1, or an antipode thereof, or an addition salt thereof with a pharmaceutically acceptable acid or base. 11. A method of preparing a compound of formula (I) according to claim 1 wherein the isomers of the protected amino acid of formula (II) are optionally separated by standard separation methods: Chemical 8] Wherein R ′ ₁ is a linear or branched (C ₁ -C ₆ ) acyl, benzyl, linear or branched (C ₁ -C ₆ ) alkoxycarbonyl, benzyloxycarbonyl or phenoxycarbonyl group, and R ₂ and R ′ ₂ have the same meaning as in formula (I),
Is a second protected amino acid of formula (III) HA-CO ₂ CH ₂ C ₆ H ₅ (III), the isomers of which have been separated by the peptide bond method and optionally by standard separation methods. Wherein A has the same meaning as in formula (I), and is reacted with a compound of formula (IV): Wherein R ′ ₁ , R ₂ , R ′ ₂ and A have the same meanings as described above, and deprotect the acid functional group by catalytic hydrogenation to give a compound of formula (V) Compound: Wherein R ′ ₁ , R ₂ , R ′ ₂ and A have the same meanings as described above, which is produced in the presence of 1,3-dicyclohexylcarbodiimide in an anhydrous medium,
The compound of formula (VI) is reacted with N-hydroxysuccinimide: In the formula, R ′ ₁ , R ₂ , R ′ ₂ and A have the same meanings as described above, and Suc means a succinimide group, and the formula (VII) is generated in a basic medium. ) Compound: In the formula, R ′ ₃ is one of the following groups: Substituted with a halogen atom, a straight chain or branched (C ₁ -C ₆ ) alkoxy, phenoxy, tetrahydro-2-furyl or cycloalkyl group. has been is a straight chain or branched chain (C ₂ -C ₄₎ alkyl, - (C ₃ -C ₇₎ cycloalkyl, - are respectively substituted with a halogen atom or a suitably protected amino group, phenyl or benzyl R ′ ₄ and R ′ ₅ are each a straight chain or a branched chain (C _1-
A C ₆ ) alkyl group, or Reacts with to form a boronic ester of pinanediol to produce any of the following: -a special case of compounds of formula (I), formula (I /
Compound of a): Where R ′ ₁ , R ₂ , R ′ ₂ , A, R ′ ₄ and R ′ ₅
Has the same meaning as described above, and R ′ _3a represents a linear or branched (C ₂ -C ₄ ) alkyl group (linear or branched (C ₁ -C ₆ ) alkoxy, phenoxy, tetrahydro- 2-furyl or (C ₃ -C ₇₎ substituted with a cycloalkyl group), or (a C ₃ -C ₇₎ cycloalkyl group, or - a compound of formula (VIII): embedded image Where R ′ ₁ , R ₂ , R ′ ₂ , A, R ′ ₄ and R ′ ₅
Has the same meaning as described above, _R'3b is one of the following groups: - substituted with halogen atoms (C ₂ -C ₄₎ alkyl, - halogen atoms or suitable respectively is substituted with protected amino group, phenyl or benzyl, wherein the, _R'3b, one of the following groups: - alkyl substituted by halogen atom, - are each substituted with a halogen atom , Phenyl or benzyl: The compound of formula (VIII) is converted to the corresponding cyanide by the action of copper cyanide and then by the action of aqueous ammonia the special compound of formula (I) The corresponding amidino compound of formula (I / b) is: Where R ′ ₁ , R ₂ , R ′ ₂ , A, R ′ ₄ and R ′ ₅
Has the same meaning as described above, _R'3c is alkyl which is respectively substituted by an amidino group, a phenyl or benzyl group, converted to, _R'3b is - is substituted with a halogen atom When it is an alkyl group, it is converted to the corresponding azide compound by the action of sodium azide, and then by catalytic hydrogenation, a special case of the compound of formula (I), corresponding to the formula (I / c) Or a phenyl or benzyl group, each of which is substituted with a protected amino group, is deprotected to provide a special case of formula (I), formula (I /
Compound of c): Where R ′ ₁ , R ₂ , R ′ ₂ , A, R ′ ₄ and R ′ ₅
Has the same meaning as described above, and R ′ _3d is an alkyl, phenyl or benzyl group, each of which is substituted with an amino group, wherein the compound of formula (I / c) is A compound of formula (I / d), which is a special case of a compound of formula (I), is converted into a guanidino group in which the amino group of the group R ′ _3d is converted by reaction with cyanamide: Where R ′ ₁ , R ₂ , R ′ ₂ , A, R ′ ₄ and R ′ ₅
Has the same meaning as described above, and R ′ _3e is an alkyl, phenyl or benzyl group, each of which is substituted with a guanidino group, and, if necessary, formula (I / a), ( I / b), (I / c) or (I / d) of the compound of formula (I) is deprotected at the terminal amine group and boron trichloride is used in an inert medium. A special case, formula (I / e): In the formula, R ′ ₁ , R ₂ , R ′ ₂ , A, and R ₃ have the same meanings as in formula (I), and are converted to the boronic acid of formula (I / a), ( A compound of I / b), (I / c), (I / d) or (I / e) is optionally purified by standard purification methods, and-if necessary, its pair by standard separation methods. A method of separating the palm body, which is appropriately converted into an addition salt with a pharmaceutically acceptable acid or base. 12. A trypsin-like serine protease inhibitor which comprises as active ingredient at least one compound according to any one of claims 1 to 10. 13. The inhibitor according to claim 12, wherein the trypsin-like serine protease inhibitor is a thrombin inhibitor.